Project summary Fanconi Anemia (FA) is a devastating genetic disease characterized by progressive bone marrow failure, birth defects and cancer susceptibility. The clinical outcomes in terms of morbidity and mortality remain poor and the pharmacological therapy of FA has not changed in over 30 years. In the past funding period we identified multiple novel small molecules and therapeutic targets that have beneficial effects in FA models. In this project we will follow up on the following candidates: 1) metformin (Aim1), P38-MAPK inhibitors (Aim 2) and combinations of small molecules (Aim 3), including those from Aims 1 and 2 as well as Project 2. We will use murine models of FA and xenotransplants (Core B) to assess the effects of these regimens on human blood progenitors in vivo. Core C will perform DNA damage assays for our project and Project 3 will test our candidates on human FA cells in vitro. In aggregate these experiments will define the therapeutic potential of small molecule monotherapy or drug combinations for the treatment of bone marrow failure in FA.